Confirmatory biomarker diagnostic studies are not needed when transitioning from NAFLD to MASLD

A multi-society Delphi consensus statement on new fatty liver disease nomenclatureJournal of HepatologyPreviewThe principal limitations of the terms nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favour of a change in nomenclature and/or definition. Full-Text PDF Open Access The new metabolic dysfunction-associated steatotic liver disease (MASLD) definition of the condition formerly known as non-alcoholic fatty liver disease (NAFLD) relies on the positive identification of a clinical phenotype of metabolic dysfunction, defined by the presence of at least one metabolic risk factor (MRF),[1]Rinella M.E. Lazarus J.V. Ratziu V. et al.A multi-society Delphi consensus statement on new fatty liver disease nomenclature.J Hepatol. 2023; Google Scholar instead of an exclusion-based, negatively defined diagnosis. It has been objected that the patient population thus identified may differ from historical NAFLD cohorts. Should that be the case, extrapolating data from previous studies on biomarkers to cohorts identified using the new patient case definition may not be possible and those studies would need to be conducted again. It has also been argued that some patients fulfilling the former NAFLD definition may not have any of the MRF criteria and may thus be missed by the new MASLD definition. The database from the AFEF Group for the Study of Liver Fibrosis was initiated starting 2011 in 5 French tertiary care centers with a research interest in diagnostic procedures for NAFLD, specifically in the diagnostic value of serum-based or imaging-based non-invasive tests (NIT) for liver fibrosis.2Cassinotto C. Boursier J. de Ledinghen V. et al.Liver stiffness in nonalcoholic fatty liver disease: A comparison of supersonic shear imaging, FibroScan, and ARFI with liver biopsy.Hepatology. 2016; 63: 1817-1827Crossref PubMed Scopus (362) Google Scholar, 3Cassinotto C. Boursier J. Paisant A. et al.Transient Versus Two-Dimensional Shear-Wave Elastography in a Multistep Strategy to Detect Advanced Fibrosis in NAFLD.Hepatology. 2021; 73: 2196-2205Crossref PubMed Scopus (20) Google Scholar, 4Cassinotto C. Lapuyade B. Guiu B. et al.Agreement Between 2-Dimensional Shear Wave and Transient Elastography Values for Diagnosis of Advanced Chronic Liver Disease.Clin Gastroenterol Hepatol. 2020; 18: 2971-2979.e3Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar, 5Paisant A. Lemoine S. Cassinotto C. et al.Reliability Criteria of Two-Dimensional Shear Wave Elastography: Analysis of 4277 Measurements in 788 Patients.Clin Gastroenterol Hepatol. 2022; 20: 400-408.e10Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar, 6Boursier J. Anty R. Vonghia L. et al.Screening for therapeutic trials and treatment indication in clinical practice: MACK-3, a new blood test for the diagnosis of fibrotic NASH.Aliment Pharmacol Ther. 2018; 47: 1387-1396Crossref PubMed Scopus (47) Google Scholar, 7Guillaume M. Moal V. Delabaudiere C. et al.Direct comparison of the specialised blood fibrosis tests FibroMeter(V2G) and Enhanced Liver Fibrosis score in patients with non-alcoholic fatty liver disease from tertiary care centres.Aliment Pharmacol Ther. 2019; 50: 1214-1222Crossref PubMed Scopus (33) Google Scholar, 8Canivet C.M. Costentin C. Irvine K.M. et al.Validation of the new 2021 EASL algorithm for the noninvasive diagnosis of advanced fibrosis in NAFLD.Hepatology. 2023; 77: 920-930Crossref PubMed Scopus (6) Google Scholar It now includes 2187 patients almost all Caucasians with liver biopsy performed for NAFLD and concomitant NIT measurements. The definition for NAFLD was the textbook definition universally used in clinical practice, consisting in the presence of steatosis with daily alcohol consumption ≤20 g in females and ≤30g in males and no other cause of chronic liver disease. We revisited the database to determine the number of patients who would not fulfill the new MASLD diagnostic criteria. We analyzed separately the entire database (N=2187) and the subcohort with no missing values for MRFs (N=1369). Table 1 shows the percentage of patients with missing data for each individual MRF. Most frequent missing data was for arterial hypertension, followed by glycemic regulation and dyslipidemia. However only 19 (0.87%) patients had missing data for all five MRFs thus precluding a diagnosis based on the MASLD definition to be made. Table 1 also shows the prevalence of patients fulfilling each individual MRF, in the entire database and in the subcohort with no missing data for any of the five MRFs. In the entire cohort, almost 97% of patients would fulfill the anthropometric adiposity based criteria, 87% the glycemic dysregulation criteria and 75%-81% the lipid panel based criteria. The estimates were almost identical in the subcohort of patients with no missing values. However, since the presence of at least one MRF is necessary for the MASLD definition, it results that, in the current state of the NAFLD database (i.e. all patients including those with unavailable parameters), at least 98.4% of patients would qualify for MASLD (Table 1). A stricter definition requiring at least two instead of a single MRF would only exclude no more than 10% of the cases in the database. When the analysis was restricted to the subcohort with no missing data, only one patient identified as NAFLD would not fulfill the MASLD definition, while 98% would still be labeled MASLD even if a stricter requirement of at least two MRF were to be required (Table 1).Table 1Number of patients fulfilling each individual metabolic risk factor or combination thereof.Metabolic risk factor (MRF)Entire database (N=2187)Subcohort with all five MRF available (N=1369)Missing data∗Missing data for respective MRF. %, (n)Criteria fulfilled#In patients with available data., % (n)Criteria fulfilled#In patients with available data., % (n)BMI ≥25 kg/m2 OR waist circumference >94 cm (M) 80 cm (F)2.2 (49)96.7 (2 067)98.4 (1347)Fasting serum glucose ≥5.6 mmol/l OR HbA1c ≥5.7% OR type 2 diabetes OR treatment for type 2 diabetes18.9 (413)87.0 (1 544)84.8 (1161)Blood pressure ≥130/85 mm Hg OR specific antihypertensive drug treatment24.5 (536)84.7 (1 399)82.5 (1130)Plasma triglycerides ≥1.70 mmol/l OR lipid lowering treatment15.3 (335)74.8 (1 386)77.8 (1065)Plasma HDL-cholesterol ≤1.0 mmol/(M) and ≤1.3 mmol/l (F) OR lipid lowering treatment15.5 (340)81.0 (1 496)84.8 (1161)No MRF present1.6 (35§Missing data for all 5 MRF in 19 patients, for 4 in 100 patients, for 3 in 110 patients, for 2 in 359 patients, for a single MRF in 330 patients.)0.1 (1)At least one MRF present98.4 (2 152)99.9 (1 368)At least two MRFs present89.8 (1 963)97.7 (1 338)At least three MRFs present77.3 (1 690)92.1 (1 261)At least four MRFs present58.3 (1 275)79.3 (1 085)All five MRFs present37.1 (812)59.3 (812)M: males; F: Females.∗ Missing data for respective MRF.# In patients with available data.§ Missing data for all 5 MRF in 19 patients, for 4 in 100 patients, for 3 in 110 patients, for 2 in 359 patients, for a single MRF in 330 patients. Open table in a new tab M: males; F: Females. Finally, we analyzed whether the AUROC for significant fibrosis and for cirrhosis for two of the most common NITs, namely VCTE and FIB4 differ according to the definition of the included population, NAFLD vs MASLD, in both the entire cohort and the subcohort with no missing values. Supplementary Table 1 shows that the diagnostic accuracy for these NITs in the MASLD-defined population is almost identical to the one in the NAFLD population. In conclusion, here we show an almost entire overlap between the population historically identified as NAFLD and the population defined by the new MASLD diagnostic criteria. This demonstrates that investigators were most probably already using exposure to MRF as a tool to identify NASH patients, which is in fact in agreement with the most recent guidelines.9Cusi K. Isaacs S. Barb D. et al.American Association of Clinical Endocrinology Clinical Practice Guideline for the Diagnosis and Management of Nonalcoholic Fatty Liver Disease in Primary Care and Endocrinology Clinical Settings: Co-Sponsored by the American Association for the Study of Liver Diseases (AASLD).Endocr Pract. 2022; 28: 528-562Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar, 10Rinella M.E. Neuschwander-Tetri B.A. Siddiqui M.S. et al.AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease.Hepatology. 2023; 77: 1797-1835Crossref PubMed Scopus (82) Google Scholar, 11EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease.J Hepatol. 2016; 64: 1388-1402Abstract Full Text Full Text PDF PubMed Scopus (2897) Google Scholar, 12EASL. EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis - 2021 update.J Hepatol. 2021; 75: 659-689Abstract Full Text Full Text PDF PubMed Scopus (428) Google Scholar While anthropometric criteria were almost always documented, other MRF were missing in 15-25% of cases. As the MASLD nomenclature gains traction, an exhaustive identification of all MRF should be implemented in future studies. Since the new nomenclature only requires a single MRF to be present, the MASLD-defined population and the historical NAFLD-defined population are almost identical rendering confirmatory studies on NITs unnecessary when transitioning from NAFLD to MASLD. JB analysis of the data, VR writing of the text, both authors, editing of the final version. None for this article. VR: none for this study. Consulting for Novo-Nordisk, Madrigal, Intercept, Sagimet, Enyo, Terns, Northsea, Hepion. Research grants (to institution) Gilead Sciences, Intercept Pharma. JB: Consulting for Astra Zeneca, Echosens, Intercept, Siemens; advisory board: Bristol-Myers-Squibb, Intercept, Pfizer, MSD, NovoNordisk; Speaker: Abbvie, Gilead, Intercept, Siemens; Funds for scientific research: Diafir, Echosens, Intercept, Inventiva, Siemens. The following is/are the supplementary data to this article. Download .docx (.02 MB) Help with docx files